Multinational comparison study of aircraft pilot healthcare avoidance behaviour.

BACKGROUND: US and Canadian pilots are required to meet medical standards to secure their active flying status, but a subgroup exhibit healthcare avoidance behaviour due to fear of loss of that status. This phenomenon has the potential to impact pilot health, aeromedical screening and aviation safety. No international comparison study of pilot healthcare avoidance currently exists between US and Canadian pilots. AIMS: To compare the rate and subtypes of healthcare avoidance behaviour secondary to fear for loss of flying status between US and Canadian pilots. METHODS: A comparison analysis of data collected during two independent, non-probabilistic, cross-sectional internet surveys including any individual certified to perform flying duties in the USA (US survey) or Canada (Canadian survey). RESULTS: There were 4320 US pilots and 1415 Canadian pilots who completed informed consent and 3765 US pilots and 1405 Canadian pilots were included in the results. There were 56% of US pilots who reported a history of healthcare avoidance behaviour compared to 55% of Canadian pilots (P = 0.578). A multivariable logistic regression that included age, pilot type and gender showed that US pilots were slightly more likely than Canadian pilots to report this behaviour (odds ratio 1.22, 95% confidence interval 1.06-1.4). CONCLUSIONS: Healthcare avoidance behaviour due to fear of loss of flying status has a relatively high prevalence in both US and Canadian pilot populations.

Limited impacts of truck-based ultra-low-volume applications of mosquito adulticides on mortality in honey bees (Apis mellifera).

Adulticides applied against mosquitoes can reduce vector populations during times of high arbovirus transmission. However, impacts of these insecticides on pollinators and other non-target organisms are of concern to mosquito control professionals, beekeepers and others. We evaluated mortality of Culex quinquefasciatus and Apis mellifera when caged insects were exposed to low and high label rates of four common adulticides (Aqua-Pursuit™ [permethrin], Duet® [prallethrin + sumithrin], Fyfanon® [malathion] and Scourge® [resmethrin]) at six distances up to 91.4 m from a truck-mounted ultra-low-volume sprayer. Honey bee mortality was both absolutely low (61 m had limited impacts on honey bee mortality while providing effective mosquito control.

Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Decreased dopamine activity predicts relapse in methamphetamine abusers.

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.

N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.

Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.

Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.

Ventricular obstruction: effect on drinking induced by intracranial injection of angiotensin.

Lesions of the subfornical organ (SFO) severely attenuated drinking induced by injections of angiotensin II into the lateral ventricles, but a few days (4 to 14) later a recovery of the drinking response is observed. A possible explanation for this is that other dipsogenic sites are involved which are beyond the interventricular foramen and that SFO lesions produce an obstruction by edema or debris at the foramen which blocks access of cerebrospinal fluid-borne angiotensin to those sites. This hypothesis is supported by tracer studies and by direct injection into the third ventricle of SFO-lesioned animals. Other studies reported implicate the anteroventral third ventricle as a likely site for angiotensin receptors.

Effects of sevoflurane on cognitive deficit, motor function, and histopathology after cerebral ischemia in rats.

BACKGROUND: The volatile anesthetic sevoflurane exhibits neuroprotective properties when assessed for motor function and histopathology after cerebral ischemia in rats. Damage of hippocampal neurons after ischemia relates to a number of cognitive deficits that are not revealed by testing animals for motor function. Therefore, the present study evaluates cognitive and behavioral function as well as hippocampal damage in rats subjected to cerebral ischemia under sevoflurane compared with fentanyl/nitrous oxide (N(2)O)/O(2) anesthesia. METHODS: Thirty-four rats were trained for 10 days using a hole-board test to detect changes in cognitive and behavioral function. Rats were randomly assigned to the following groups: (A) sham/fentanyl/N(2)O/O(2) (n=7); (B) ischemia/fentanyl/N(2)O/O(2) (n=10); (C) sham/2.0 vol% sevoflurane in O(2)/air (n=7); and (D) ischemia/2.0 vol% sevoflurane in O(2)/air (n=10). Cerebral ischemia was produced by unilateral common carotid artery occlusion combined with hemorrhagic hypotension (mean arterial blood pressure 40 mmHg for 45 min). Temperature, arterial blood gases, and pH were maintained constant. Cerebral blood flow was measured using laser-Doppler flowmetry. After surgery, cognitive and behavioral function was re-evaluated for 10 days. On day 11, the brains were removed for histopathologic evaluation (hematoxylin/eosin-staining). RESULTS: Cognitive testing revealed deficits in declarative and working memory in ischemic rats anesthetized with fentanyl/N(2)O. Rats anesthetized with sevoflurane during ischemia showed a significantly better outcome. Hippocampal damage was significantly worse with fentanyl/N(2)O. CONCLUSION: The present data add to previous investigations showing that sevoflurane prevents a deficit in cognitive function and histopathological damage induced by cerebral ischemia in rats.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Immunoglobulin G3 subclass production by rheumatoid synovial tissue cultures.

The cellular infiltrate in the deeper layers of the rheumatoid synovium produces a substantial amount of immunoglobulin (Ig)G. Culture supernatants of synovial tissues from 31 patients with rheumatoid arthritis (RA) undergoing joint replacement or synovectomy have been analyzed for the subclass of IgG present. IgG3 was measured by separation with Staphylococcal Protein A chromatography, precipitation with specific anti-IgG3 antibody, and differential separation of IgG3 heavy chains using polyacrylamide gel electrophoresis. IgG from RA synovial cultures contained an average of 41% IgG3 (range, 8-97%) compared with 12% IgG3 (range, 6-17%) in the serum IgG of the same patients. A group of non-RA control lymphoid tissues (four lymph nodes and five tonsils) produced 23% of total IgG as the IgG3 subclass (range, 16-35%). An average of only 9% of the synovial IgG showed aggregation compatible with IgG-rheumatoid factor (IgG-RF). Purified IgG from some of the RA synovial culture supernatants also showed significant restriction when separated by isoelectric focusing. This restriction and the enrichment for the IgG3 subclass in the IgG from RA synovial cultures suggest that either an antigen in the inflamed joint is selectively stimulating an antibody in this subclass, or that significantly differences in the catabolic rate of this subclass are found in cultures of synovial tissue when compared with that occurring in intact patients.

Human prolactin and thyrotropin concentrations in the serums of normal and hypopituitary children before and after the administration of synthetic thyrotropin-releasing hormone.

Synthetic thyrotropin-releasing hormone (TRH) was administered to normal children and hypopituitary patients in a dose of 7 mug/kg i.v. over 30-60 sec. Serum thyrotropin (TSH) and prolactin (HPr) concentrations were measured by radioimmunoassay before and at 15-min intervals for 2 hr after TRH. In 20 normal children HPr rose from a mean baseline value of 7.0+/-1.2 (SEM) ng/ml to a mean peak value of 39.5+/-5 ng/ml. In 11 patients with growth hormone (GH) deficiency without TSH deficiency. HPr values rose from a mean baseline of 3.6+/-0.8 ng/ml to a mean peak value of 13.9+/-2.8, a significantly less peak response as compared with normal children (P < 0.005). The TSH responses to TRH, however, were statistically indistinguishable from those of normal children. In 10 patients with GH and TSH deficiency both the mean baseline HPr levels (25.0+/-5 ng/ml) and the mean peak HPr levels after TRH (68.5+/-10 ng/ml) were significantly higher (P < 0.005 and < 0.025) than those of normal children. Similar comparisons were also true for the peak TSH responses (P < 0.05). Two panhypopituitary patients released no TSH and only small amounts of HPr after TRH. After thyroid replacement therapy in eight of the patients with GH and TSH deficiency, the mean HPr baseline levels (7.6+/-1.0 ng/ml) and peak levels (23.3+/-4.6 ng/ml) after the same dose of TRH were significantly less than their pretreatment levels (P < 0.001 and < 0.01) and were within the range for normal children. Synthetic TRH stimulates the simultaneous release of TSH and HPr in normal children and most hypopituitary patients. When the concentrations of thyroxine (T4) and triiodothyronine (T3) are low, the levels of HPr before and after TRH are elevated. After thyroid replacement therapy, HPr levels decrease to normal. T4 and/or T3 may condition the production or effects of prolactin-inhibiting factor (PIF) activity. The TSH and HPr responses after TRH in hypopituitary patients will determine whether the primary defect resides in the pituitary or hypothalamus, but cannot delineate the hypothalamic defect as a deficiency of hypothalamic hormone production or neurohumoral transmission.

The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation.

While the transactivation function of the tumor suppressor p53 is well understood, less is known about the transrepression functions of this protein. We have previously shown that p53 interacts with the corepressor protein mSin3a (hereafter designated Sin3) in vivo and that this interaction is critical for the ability of p53 to repress gene expression. In the present study, we demonstrate that expression of Sin3 results in posttranslational stabilization of both exogenous and endogenous p53, due to an inhibition of proteasome-mediated degradation of this protein. Stabilization of p53 by Sin3 requires the Sin3-binding domain, determined here to map to the proline-rich region of p53, from amino acids 61 to 75. The correlation between Sin3 binding and stabilization supports the hypothesis that this domain of p53 may normally be subject to a destabilizing influence. The finding that a synthetic mutant of p53 lacking the Sin3-binding domain has an increased half-life in cells, compared to wild-type p53, supports this premise. Interestingly, unlike retinoblastoma tumor suppressor protein, MDMX, and p14(ARF), Sin3 stabilizes p53 in an MDM2-independent manner. The ability of Sin3 to stabilize p53 is consistent with the model whereby these two proteins must exist on a promoter for extended periods, in order for repression to be an effective mechanism of gene regulation. This model is consistent with our data indicating that, unlike the p300-p53 complex, the p53-Sin3 complex is immunologically detectable for prolonged periods following exposure of cells to agents of DNA damage.

Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation.

Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.

Carcinogenicity studies of fluoxetine hydrochloride in rats and mice.

The antidepressant drug fluoxetine HCl was tested for carcinogenicity in three well designed and controlled studies in Fischer rats and C57BL/6 x C3H F1 mice. The compound was administered to the animals for 24 months at dietary doses of approximately 0, 0.5, 2.0, or 10.0 mg/kg body weight in rats and 1.0, 5.0, or 10.0 mg/kg in mice. The highest dose tested was a maximum tolerated dose for both species as evidenced by clinical signs (rats and mice) and some mortality (mice) referable to central nervous system pharmacological effects, decreased weight gain (rats), and histopathological changes of phospholipidosis (rats) and hepatic fatty change (mice). There was no evidence of an increased incidence of any type of unusual or commonly occurring spontaneous neoplasm in either rats or mice. There were statistically significant decreases in a few commonly occurring neoplasms. The data reported herein provide convincing evidence that fluoxetine is neither a complete carcinogen nor a tumor promoter.

Analysis by two-dimensional polyacrylamide gel electrophoresis of liver ribosomal subunnit proteins obtained from free and membrane-bound polysomes of unfasted animals.

Ribosomal proteins were analyzed by means of two-dimensional gel electrophoresis. To insure that the analysis included only that fraction of the ribosome actively participating in protein synthesis, only polysomal-bound ribosomes were used. This differs from previously reported analyses of liver ribosomal proteins. The ribosomal proteins were prepared from ribosomes of polysomal origin from membrane-bound and free polysomes. Membrane-bound and free liver polysomes were isolated from unfasted mice. The polysomes were purified on hydroxyapatite under conditions known to result in polysomes and ribosomes that are active in both endogenous and synthetic mRNA translation. Moreover, this is the first time that liver ribosomal protein was obtained and analyzed from animals that have not been starved prior to sacrifice. The puromycin-released ribosomes were dissociated into subunits and ribosomal proteins were analyzed by means of two-dimensional polyacrylamide gel electrophoresis. When 100-200 mug samples of the ribosomal subunit proteins were analyzed by two-dimensional electrophoresis, approximately 32 major proteins were detected for the 60 S ribosomal subunit and 25 major proteins for the 40 S ribosomal subunit. A total of 13 "fractional" ribosomal proteins was also detected in the ribosomal subunit profiles. No differences in number or mobility of the ribosomal proteins were found between the membrane-bound and free ribosome populations. We describe a system in which all ribosomal proteins are completely solubilized and quantitatively move from the first to the second dimension gel. Thus the total sample is separated and fractionated. This procedure elimates artifacts due to incomplete solubilization of ribosomal proteins, which is common for the transfer from the first- to second-dimension gel. Therefore, a more detailed and accurate analysis is achieved.

Chemical modification of tyrosyl and lysyl residues in goat alpha lactablbumin and the effect on the interaction with the galactosyl transferase.

The effect of acylation of goat alpha-lactalbumin on lactose synthetase activity and the ability of alpha-lactalbumin to inhibit the transfer of galactose to N-acetylglucosamine is biphasic. Approx. 15% of the lactose synthase activity of goat alpha-lactalbumin and 10% of its inhibitory power is lost in the initial phase, with corresponding losses of 65 and 30% in the second phase. Deacylation of reacted tyrosyl groups with hydroxylamine restored inhibitory power completely in the initial phase and partially in the second phase. Removal of acyl groups in the initial phase decreased lactose synthase activity, but had no effect in the second phase. The differential effect of acylation of alpha-lactalbumin on lactose synthase and inhibitory properties appears to be the result of differential changes in the affinity of the UDP-Gal-galactosyl-transferase-alpha-lactalbumin ternary complex for monosaccharides.

Correlates of brain edema in uncontrolled IDDM.

Blood glucose, plasma sodium, bicarbonate (HCO3-), vasopressin, and hematocrit were monitored before and during treatment in patients with uncontrolled insulin-dependent diabetes mellitus (IDDM). These parameters were correlated with simultaneous serial cranial computed tomography readings of brain edema. Six of seven patients had positive computed tomography readings for brain edema on admission. Initial brain edema correlated directly with blood glucose (r = 0.79, P = 0.033) and inversely with HCO3- (r = -0.76, P = 0.047). At 6 h, brain edema still correlated with acidosis (HCO3-; r = -0.79, P = 0.033) but no longer with blood glucose. At that time, however, brain edema correlated with the rate of change in blood glucose (r = 0.915, P = 0.005). Results of interactive stepwise regression analysis suggest that the change in the calculated effective plasma osmolality plays a predominant role in the progression of brain edema during therapy (r = 0.995, P less than 0.001). Thus, although hyperglycemia and acidosis probably predispose to diabetic brain edema, osmotic factors may be major predictors of its evolution. No relationships were detected between brain edema and initiation of insulin therapy, plasma vasopressin, or changes in hematocrit. The factors responsible for initial brain edema and its progression, statistically identified in this study, require reassessment of common theories that attribute brain edema exclusively to therapy.

Retinopathy in juvenile-onset type I diabetes of short duration.

We evaluated the prevalence and severity of diabetic retinopathy in 173 juvenile-onset, type I diabetic subjects and 78 nondiabetic controls of similar age, race, and sex distribution by stereoscopic fundus photography and fluorescein angiography, performed by a standardized protocol and evaluated by five expert, masked observers. The overall prevalence of retinopathy was 18% in the diabetic group and 0% in the controls. Retinopathy prevalence increased with duration of diabetes in the diabetic group, with a prevalence of 1% from 0--4 yr after diagnosis, 25% after 5--9 yr, and 67% 10--16 yr after onset of the systemic disease. There was an independent association with age, with little retinopathy before age 15 and a 48% prevalence in older persons. Retinopathy was also found to be independently associated with the following: diabetic "control," evaluated semiquantitatively but on a masked basis; lens opacities; and frequency of daily insulin injections. Among the 166 diabetic subjects who had both angiography and photography, a retinopathy prevalence of 17% was detected by angiography and 11% by photography. This difference was statistically significant (P = 0.01). This study provides baseline data for use in estimating sample size in controlled trials of therapeutic measures to prevent retinopathy in juvenile diabetic populations. The study also supports the hypothesis that long-term hyperglycemia as well as changes (possibly hormonal in nature) associated with puberty are causally related to diabetic retinopathy.

The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study.

In a controlled study, we compared the prevalence of tardive dyskinesia in 38 neuroleptic-treated diabetics with the prevalence of tardive dyskinesia in a group of 38 nondiabetic neuroleptic-treated controls, matched for age, sex, psychiatric diagnosis, and dose and duration of neuroleptic treatment. Members of each group were evaluated for movement disorders by a rater who used standard rating scales and was "blind" to all diagnoses and treatments. Neuroleptic-treated diabetics had a significantly higher prevalence and severity of tardive dyskinesia. There were no differences between groups on other possible risk factors for tardive dyskinesia, including parkinsonism, anticholinergic drug treatment, or cognitive function. These data suggest that diabetes mellitus should be examined further as a risk factor for tardive dyskinesia.